History

A 35 year-old African-American man presented from prison in southwestern Ohio with two weeks of shortness of breath, productive cough with yellow sputum, daily fevers, drenching sweats, unintentional weight loss of 20 pounds, and malaise. He had been incarcerated for 4.5 years, and had not left the prison during that time. He denied tuberculosis exposure or history of a positive purified protein derivative (PPD). He noted several inmates recently diagnosed with pneumonia. It was notable that the outdoor yard at the prison had many pigeons.

His past medical history was significant only for a testicular abscess. His social history was positive for smoking three cigarettes daily since the age of 15. He had no family history of pulmonary disease or malignancy. He did not take any prescription or over the counter medications, and had no known drug allergies.

Physical Exam

On physical examination, his temperature was 100.5oF, pulse was 103, respiratory rate was 18, blood pressure was 136/80, and oxygen saturation was 93% on 2 liters/nasal cannula. Weight was 85.6kg with of height 1.78 meters. He was alert and oriented, and was visibly sweating. His neck showed no elevation of jugular venous pulsations. His mouth showed moist mucous membranes. Pulmonary exam was clear to auscultation bilaterally in the posterior and anterior lung fields. Cardiac exam revealed a regular, tachycardia rhythm with a heart rate of 103, and no murmurs, rubs, or gallops. Extremities had no edema and equal distal pulses bilaterally. Testicular exam showed no testicular swelling or pain. Cutaneous exam showed diaphoretic skin without any rashes or lesions.

Question 1

Which of the following can present with the pattern of infiltrates seen in Figures 1 & 2 above?

A.

Fungal Infection Incorrect!

B.

Hematogenous spread of non-pulmonary lung cancer Incorrect!

C.

Miliary tuberculosis Incorrect!

D.

Pneumoconiosis Incorrect!

E.

Primary lung cancer Incorrect!

F.

All of the above Correct!

Answer: F

The infiltrates seen on both the chest x-ray and CT are consistent with a miliary pattern. While miliary tuberculosis would be high on the differential especially given the history of incarceration, fevers, sweats, and cough, the differential diagnosis is quite broad. Bronchoalveolar carcinoma can manifest with similar radiographic findings, and associated systemic symptoms such as fatigue, fever, night sweats, and weight loss. Fungal infections such as histoplasmosis, coccidiomycosis, and blastomycosis could be considered based on recent travel and geographic location to endemic areas. Pneumoconiosis can have diffuse miliary infiltrates, however would not be suspected to have the associated fevers, chills, and sweats. Hematogenous spread of non-pulmonary cancers can also present with this pattern on chest imaging.(1-7)

Question 2

Of the following primary malignancies, which would most likely be associated with a diffuse miliary pattern on chest imaging?

A.

Brain Incorrect!

B.

Breast Incorrect!

C.

Liver Incorrect!

D.

Renal Correct!

E.

Prostate Incorrect!

Answer: D

Of the above primary solid organ malignancies, renal would be the most likely to present with a miliary infiltrate on chest imaging. Thyroid cancer, melanoma, trophoblastic tumors, sarcomas, and leiomyoma have been known to have hematogenous spread to the lungs and display a miliary pattern (5, 6). As clinical symptoms of shortness of breath, fever, chills, malaise, fatigue, cough can be non-specific and present in many conditions including infection and malignancy, tissue diagnosis becomes crucial to establishing a definitive diagnosis.

History Continued:

The patient was placed in respiratory isolation and had three sputum cultures collected. The sputum smears were negative for acid fast bacilli. Serum levels of beta-human chorionic gonadotropin (HCG) and alpha fetoprotein (AFP) were obtained and were within normal limits. A Mycobacterium Tuberculosis by Quantiferon was indeterminate due to low control response, and the Human Immunodeficiency Virus (HIV) Antibody test was non-reactive. He subsequently underwent bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial biopsy. BAL cell differential revealed 80% alveolar macrophages, 7% neutrophils, 12% lymphocytes, and 0% eosinophils. Cultures were negative. Urinary blastomyces antigen returned positive at 1.59 ng/mL (0.2-14.7 ng/mL positive range of detection).

Question 3

Which of the following laboratory tests has the highest percentage of diagnostic yield for blastomycosis in this patient?

A.

Biopsy Correct!

B.

Complement fixation Incorrect!

C.

Cytology Incorrect!

D.

Direct examination of secretions Incorrect!

E.

Respiratory culture Incorrect!

F.

Urinary antigen testing Incorrect!

Answer: A

Blastomycosis is a systemic disease caused by blastomyces dermatitidis, which is a dimorphic fungus. Initial infection is via the pulmonary tract from inhalation of spores. Often, infection is subclinical or goes unrecognized as pneumonia, however acute pneumonia is common and can mimic viral or bacterial pneumonias. Typically there is an abrupt onset and associated myalgias, arthralgias, chills, and fever. Usually there is recovery, however this can progressive to chronic pulmonary disease which is characterized by hemoptysis, weight loss, pleuritic chest pain, productive cough, and low grade fevers. Chest radiography can show miliary pattern, lobar pattern, mass like lesion, or cavitation. Extra pulmonary manifestations most commonly include skin lesions (40-80%) such as ulcerations, verrucous lesions, or subcutaneous nodules. Osteomyelitis, prostatitis, and epididymitis are all reported in association to blastomycosis(9).

Direct examination of respiratory secretions have a 36% yield for a single specimen, and 46% yield for multiple specimens. Addition of 10% potassium hydroxide to specimen may increase yield. Cytology may provide a diagnosis in 56-72% of cases in pulmonary blastomycosis. Respiratory culture has a higher yield than direct visualization of secretions, with 75% chance of positive culture with a single specimen, and 86% with multiple specimens per patient. These may be as high as 92% when respiratory culture obtained via bronchoscopy (9, 10). Urinary blastomycosis antigen is higher than serum, and has a sensitivity of 93%, and sensitivity of 79.3% (9-11). There can be cross-reactivity with Histoplasma capsulatum (5%), aspergillus species (5%) and Cryptococcus neoformans (2%). Biopsy can have a near 100% sensitivity for detecting disease, and is considered the gold standard. Serological testing with immune-diffusion or complement fixation does not yet have enough clinical data for routine use (10, 12, 13).

Question 4

Which of the following treatments would you recommend for first line treatment of pulmonary blastomycosis in this patient?

A.

Amphotericin B Incorrect!

B.

Fluconazole Incorrect!

C.

Itraconazole Correct!

D.

Ketoconazole Incorrect!

E.

Metronidazole Incorrect!

Answer: C

For mild to moderate pulmonary blastomycosis infection, itraconazole at a dose of 200mg once to twice daily for six to twelve months is recommended. For moderately severe to severe pulmonary blastomycosis, liposomal amphotericin B is recommended in 3-5mg/kg per day dosing for one to two weeks, following by itraconazole for six to twelve months. For those patients who are immunosuppressed, liposomal amphotericin should be used for four to six weeks prior to transition to itraconazole for one year. Pregnant females should be treated with liposomal amphotericin and azoles should be avoided during the pregnancy. Itraconazole is preferred over ketoconazole due to the side effect profile and variable absorption. Itraconazole has a higher success rate as compared to fluconazole. Metronidazole is not used for treatment of pulmonary blastomycosis. (9, 10)

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